Contrast agent



United States Patent CONTRAST AGENT Domenick Papa, Bloomfield, and Helen Florence Ginsberg, Montclair, N. 1., .assignors .to Schering Corporation, Bloomfield, N. 3., a corporation of New Jersey No Drawing. Application May 13, 1952, Serial No. 287,624

10 Claims. (Cl. 167-95) This invention relates to a new group of compounds having contrast properties. More particularly, the invention relates to polyiodinated phenyl fatty acids and their non-toxic metal and amine salts having a definite selectivity for visualization of the gall bladder.

It is known that all X-ray diagnostic agents for gall bladder visualization which have gone into clinical use contain an amino or 'hydroxyl group attached to a halogen-carrying aromatic ring. These groups are, however,

wherein R is an alkyl group having from 1 to carbon atoms, and n is 3 or 4, and their non-toxic alkali and alkaline earth metal salts, preferably the sodium salts, and

their non-toxic amine salts, like the alkylolarnine, e. g. diethanolamine salts, and the dialkylamine, e. g. diethylamine salts.

The compounds of the present invention are prepared by diazotizing the appropriate amino derivative and replacing the diazonium group either with hydrogen or with iodine. The following equations are illustrative of these transformations:

NaNOz H CHaC-COOH I I l l CzHsOH Gu and I HaCh-COOH CHzC.COOH

II III "ice For the replacement of the amino group by iodine, the following equations illustrate the procedures:

CH; CH:

The compounds of the invention may be used in the form of the free acids or in the form of their salts. They may be dispensed either in tablet form using inert carriers like the usual starch, gums, sugars and the like, or may be combined with edible emulsifiers for use'in fluid form. The dosage is A to /2 that for known gall bladder contrast agents, such as Priodax (oa-phenyl-fl-(3,5- diiodo-4-hydroxy-phenyl)-propionic acid). 7

The following examples illustrate in greater detail satisfactory methods for the preparation of the compounds of the invention, but are not intended to indicate the scope of the invention.

EXAMPLE I a-Ethyl- 8(2,4,6-triiodophenyl) propionic acid To a refluxing solution of 5.0 g. of methyl- 542,45- triiodo-3-arninophenyl) propionic acid (J. Amer. Chem.

Soc. 71, 3753 (1949)) in 60 ml. of benzene, 13 ml. of ethanol and 2.5 ml. of concentrated sulfuric acid, are added, portionwise, 2.5 g. of powdered sodium nitrite. When the ensuing evolution of nitrogen diminishes, most of the solvents are removed by distillation and the residue allowed to stand overnight at room temperature. The solid is filtered off and, after washing with warm water, is recrystallized from benzene-petroleum ether to yield methyl-d(2,4,6-triiodophenyl) propionic acid.

An alternative synthesis of this compound is carried out by diazotizing a chilled solution of 5.0 g. of methylfl-(2,4,6-triiodo-3-anrinophenyl) propionic acid in 45 ml. of concentrated sulfuric acid with 2.5 g. of solid sodium nitrite. After standing for two hours at C., the solution is poured over 200 g. ice and the aqueous solution slowly added to a suspension of 2 g. of cuprous oxide in 150 ml. of cold alcohol. After the initial evolution of nitrogen diminishes, the mixture is refluxed until the nitrogen evolution ceases. The mixture is then cooled, poured into water and the resulting precipitate filtered. After extracting the solid with ether, the ether layer is washed with sodium thiosulfate solution and dried over sodium sulfate. Evaporation of the solvent followed by recrystallization of the residue from chloroform-petroleum ether yields a-ethyl-fl-(2,4,6-triiodophenyl)propicnic acid.

EXAMPLE II ot-Ethyl-B-(3,4,5-triiod0phenyl) propionic acid To a chilled solution of 3.5 g. of a-etl1yl-;8-(3,5-di-- iodo 4 aminophenyDpropionic acid (J. Amer. Chem. Soc., 71, 3753 (1949)) in concentrated sulfuric acid are added, portionwise, 2.0 g. of powdered sodium nitrite. After standing for two hours at 0, the solution is poured on ice and then a solution of 9.0 g. of potassium iodide in 20 ml. of water is added slowly. The mixture is heated on a steam bath until the evolution of nitrogen ceases, and then poured into a saturated sodium bisulfite solution. The precipitate is filtered off, washed with water and recrystallized from acetone to give the triiodo acid of this example.

EXAMPLE III oc'Et/lyl-B-(2,3,4,6-t tfaiodophenyl) propionic acid The amino group in methyl-p-(2,4,6-triiodo-3-aminophenyl) propionic acid is diazotized and replaced by iodine according to the method of Example II to give this tetraiodo acid, recrystallizable from benzene.

EXAMPLE IV ot-Ethyl-B-(2,4,5-triiodophenyl) propionic acid The requisite intermediate, u-ethyhB-(2,4-diiodo-5- aminophenyl) propionic acid, is prepared as follows:

To a stirred solution of 19.3 g. of ot-ethyl-B-(5-aminolized from aqueous methanol to yield the above-named intermediate. The amino acid is converted to the triiodo compound by the procedure of Example II.

EXAMPLE V ut-M lhyl-fi-(2,4,6-triiadophenyl) propionic acid Diazotization of a-methyl ,8 (3-amino-2,4,6 triiodophenyl) propionic acid (J. Amer. Pharrn. Assoc., 40, 618 (1951)) and replacement of the diazonium group by hydrogen according to the procedure of Example I yields the triiodo acid as a white crystalline compound after recrystallization from benzene-hexane.

4 EXAMPLE vr u-Methyl-fi-(2,4,5-trii0dophenyl) propionic acid The intermediate a-methyl-fl-(2,4-diiodo-5-aminophenyl) propionic acid is prepared from a-methyI-fi-(B-aminophenyl) propionic acid and iodine monochloride by the method described in Example IV. Diazotization of a chilled solution of 5.0 g. of the amino acid in concentrated sulfuric acid with 4.0 g. of sodium nitrite followed by treatment with a solution of 15 g. of KI in ml. of water, as described in Example II, yields the crude triiodo acid. Purification is eifected by recrystallization from acetone.

EXAMPLE VII a-Merhyl-fl- (2,3,4,6-t traiodophenyl) propionic acid This acid is obtained from zx-methyl-fi-(2,4,6-triiodo- 3-aminophenyl) propionic acid according to the procedure of Example II, as a white crystalline compound after recrystallization from benzene-petroleum ether.

EXAMPLE VIII a-Propyl-fi-(3,4,5-trii0d0phenyl) propionic acid Treatment of a solution of 4.0 g. of ot-propyl-fi-(Ii,5- diiodo-4-aminophenyl) propionic acid in ml. of concentrated sulfuric-acid with 3.0 g. of powdered sodium nitrite, followed by decomposition with ice and water yields an intermediate which is treated with 12 g. of potassium iodide in 25 ml. of water to give, according to the procedure of Example II, the above-named triiodo acid. The product is recrystallizable from benzenehexane.

EXAMPLE IX rx-Propyl-{i-(2,4,6-triiod0phcnyl) propionic acid A solution of 6 g. of u-propyl-fi-(2,4,6-triiodo-3- aminophenyl) propionic acid in 65 ml. of benzene, 15 ml. of ethanol and 3 ml. of concentrated sulfuric acid was diazotized with 3 g. of powdered sodium nitrite. After treating the resultant solution according to the procedure of Example I, the crude triiodo acid of this example was obtained and purified by recrystallization from benzenepetroleum ether.

EXAMPLE X oc-Butyl-B-(2,4,6-triiodophcnyl) propionic acid 7 A chilled solution of 5 g. of a-butyl-B-(2,4,6-triiodo- 3-aminophenyl) propionic acid in m1. of concentrated sulfuric acid was diazotized with 2.5 g. of solid sodium nitrite. After working up according to the alternative procedure of Example I, and recrystallizing from chloroform-petroleum ether, the above-named acid was obtained.

EXAMPLE XI tx-Butyl-fi-(3,4,5-trii0d0pherzyl) propionic acid Treating a chilled solution of 4 g. of a-butylf:t-(3,5- diiodo-4-aminophenyl) propionic acid in 40 ml. of concentrated sulfuric acid with 2.5 of powdered sodium nitrite, followed by iodination with a solution of 10 g. of potassium iodide in 25 ml. of water yields, according to the procedure of Example ii, the triiodo acid of this example.

EXAMPLE XII wButyl-fl- (2,3,4,6-tctraiorlopizcnyl) propionic acid A chilled solution of 4 g. of u-butyl-fl-(2,4,6-triiodo- 3-aminophenyl) propionic acid in 40 ml. of concentrated sulfuric acid is diazotized with 2.5 g. of powdered sodium nitrite, followed by iodination with a solution of 10 g. of potassium iodide in 20 ml. of water, to yield, according to the procedure of Example Ii, the tetraiodo acid as a crystalline powder recrystallizable from benzene.

Each of the above acids can readily be converted into its non-toxic alkali, and alkaline earth metal and amine salts, in known manner, to yield more or less neutral products. The preferred salts are those of sodium and of diethanolamine and diethyl amine, with each of the polyiodophenyl aliphatic acids.

From the foregoing, it will be seen that we have provided polyiodo-phenyl aliphatic acids which in the phenyl nucleus are free from solubiliz-ing substituents, and particularly from amino and hydroxy groups.

We claim:

1. An X-ray contrast agent suitable for visualization of the gall bladder by the oral route, and comprising a pharmaceutical carrier having distributed therein a mem ber of the class consisting of propionic acids of the formula wherein R is an alkyl group having from 1 to 5 carbon atoms and n is an integer from 3 to 4, and their nontoxic alkali and alkaline earth metal and amine salts.

2. An X-ray contrast agent suitable for visualization of the gall bladder by the oral route, and comprising a tablet containing a binder and a member of the group consisting of walkyl-fl-polyiodophenyl propionic acids and their non-toxic alkali and alkaline earth metal and amine salts, the number of iodine atoms being from 3 to 4 and the alkyl group containing from 1 to 5 carbon atoms.

3. An X-ray contrast agent suitable for visualization of the gall bladder by the oral route, said contrast agent being in the form of an aqueous preparation containing an edible emulsifier and a member of the group consisting of a-alkyl-fl-polyiodophenyl propionic acids and their non-toxic alkali and alkaline earth metal and amine salts, the number of iodine atoms being from 3 to 4 and the alkyl group containing from 1 to 5 carbon atoms.

4. A compound having the formula R QHiJJHOOOH wherein R is an alkyl group having from 1 to 4 carbon atoms.

5. A compound having the formula:

0 wherein. R is an alkyl group having from 1 to 4 carbon atoms.

6. a-Et'hyhfi-(2,4,6-triiodophenyl) propionic acid.

7. u-Ethyl-fi-(2,3,4,6-tetraiodophenyl) propionic acid.

8. a-Methyl-p-(2,4,6-triiodophenyl) propionic acid.

9. An X-ray contrast agent comprising a pharmaceutical carrier having distributed therein a-methyI-fl-(Z; 3,4,6-tetraiodophenyl) propionic acid.

10. u-Propyl-fl-(2,4,6-triiodopheny1) propionic acid.

References Cited in the file of thispatent UNITED STATES PATENTS OTHER REFERENCES Griess: Ber. Deut. Chem, vol. 21, pp. 978-980 (1888).

Weida: Am. Chem. J., vol. 19, pp. 552-561 (1897).

Richters Organic Chemistry, 3rd English Ed., 1946, vol. III, pages 122-123.

Mayer: Beilstein (Handbuch, 4th Ed.), vol. 9, 2nd Sup., p. 355 1949 

1. AN X-RAY CONTRAST AGENT SUITABLE FOR VISUALIZATION OF THE GALL BLADDER BY THE ORAL ROUTE, AND COMPRISING A PHARMACEUTICAL CARRIER HAVING DISTRIBUTED THEREIN A MEMBER OF THE CLASS CONSISTING OF PROPIONIC ACIDS OF THE FORMULA 